The present invention relates to the use of (xe2x88x92) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives and compositions in the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia. It further relates to (xe2x88x92) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives that are useful for the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia.
Diabetes mellitus, commonly called diabetes, refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose, referred to as hyperglycemia. See, e.g., LeRoith, D. et al., (eds.), Diabetes Mellitus (Lippincott-Raven Publishers, Philadelphia, Pa. U.S.A. 1996), and all references cited therein. According to the American Diabetes Association, diabetes mellitus is estimated to affect approximately 6% of the world population. Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk for microvascular and macrovascular diseases, including nephropathy, neuropathy, retinopathy, hypertension, cerebrovascular disease and coronary heart disease. Therefore, control of glucose homeostasis is a critically important approach for the treatment of diabetes.
There are two major forms of diabetes: Type 1 diabetes (formerly referred to as insulin-dependent diabetes or IDDM); and Type 2 diabetes (formerly referred to as non-insulin dependent diabetes or NIDDM).
Type 1 diabetes is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. This insulin deficiency is usually characterized by xcex2-cell destruction within the Islets of Langerhans in the pancreas, which usually leads to absolute insulin deficiency. Type 1 diabetes has two forms: Immune-Mediated Diabetes Mellitus, which results from a cellular mediated autoimmune destruction of the xcex2 cells of the pancreas; and Idiopathic Diabetes Mellitus, which refers to forms of the disease that have no known etiologies.
Type 2 diabetes is a disease characterized by insulin resistance accompanied by relative, rather than absolute, insulin deficiency. Type 2 diabetes can range from predominant insulin resistance with relative insulin deficiency to predominant insulin deficiency with some insulin resistance. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistant individuals, the body secretes abnormally high amounts of insulin to compensate for this defect. When inadequate amounts of insulin are present to compensate for insulin resistance and adequately control glucose, a state of impaired glucose tolerance develops. In a significant number of individuals, insulin secretion declines further and the plasma glucose level rises, resulting in the clinical state of diabetes. Type 2 diabetes can be due to a profound resistance to insulin stimulating regulatory effects on glucose and lipid metabolism in the main insulin-sensitive tissues: muscle, liver and adipose tissue. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver. In Type 2 diabetes, free fatty acid levels are often elevated in obese and some non-obese patients and lipid oxidation is increased.
Premature development of atherosclerosis and increased rate of cardiovascular and peripheral vascular diseases are characteristic features of patients with diabetes. Hyperlipidemia is an important precipitating factor for these diseases. Hyperlipidemia is a condition generally characterized by an abnormal increase in serum lipids in the bloodstream and is an important risk factor in developing atherosclerosis and heart disease. For a review of disorders of lipid metabolism, see, e.g., Wilson, J. et al., (ed.), Disorders of Lipid Metabolism, Chapter 23, Textbook of Endocrinology, 9th Edition, (W .B. Sanders Company, Philadelphia, Pa. U.S.A. 1998; this reference and all references cited therein are herein incorated by reference). Serum lipoproteins are the carriers for lipids in the circulation. They are classified according to their density: chylomicrons; very low-density lipoproteins (VLDL); intermediate density lipoproteins (IDL); low density lipoproteins (LDL); and high density lipoproteins (HDL). Hyperlipidemia is usually classified as primary or secondary hyperlipidemia. Primary hyperlipidemia is generally caused by genetic defects, while secondary hyperlipidemia is generally caused by other factors, such as various disease states, drugs, and dietary factors. Alternatively, hyperlipidemia can result from both a combination of primary and secondary causes of hyperlipidemia. Elevated cholesterol levels are associated with a number of disease states, including coronary artery disease, angina pectoris, carotid artery disease, strokes, cerebral arteriosclerosis, and xanthoma.
Dyslipidemia, or abnormal levels of lipoproteins in blood plasma, is a frequent occurrence among diabetics, and has been shown to be one of the main contributors to the increased incidence of coronary events and deaths among diabetic subjects (see, e.g., Joslin, E. Ann. Chim. Med. (1927) 5: 1061-1079). Epidemiological studies since then have confirmed the association and have shown a several-fold increase in coronary deaths among diabetic subjects when compared with nondiabetic subjects (see, e.g., Garcia, M. J. et al., Diabetes (1974) 23: 105-11 (1974); and Laakso, M. and Lehto, S., Diabetes Reviews (1997) 5(4): 294-315). Several lipoprotein abnormalities have been described among diabetic subjects (Howard B., et al., Artherosclerosis (1978) 30: 153-162).
Previous studies from the 1970""s have demonstrated the effectiveness of racemic 2-acetamidoethyl(4-chlorophenyl)(3-trifluoromethylphenoxy)acetate (also known as xe2x80x9chalofenatexe2x80x9d) as a potential therapeutic agent to treat Type 2 diabetes, hyperlipidemia and hyperuricemia (see, e.g., Bolhofer, W., U.S. Pat. No. 3,517,050; Jain, A. et al., N. Eng. J. Med. (1975) 293: 1283-1286; Kudzma, D. et al., Diabetes (1977) 25: 291-95; Kohl, E. et al., Diabetes Care (1984) 7: 19-24; McMahon, F. G. et al., Univ. Mich. Med. Center J. (1970) 36: 247-248; Simori, C. et al., Lipids (1972) 7: 96-99; Morgan, J. P. et al., Clin. Pharmacol. Therap. (1971) 12: 517-524, Aronow, W. S. et al., Clin. Pharmacol Ther (1973) 14: 358-365 and Fanelli, G. M. et al., J. Pharm. Experimental Therapeutics (1972) 180:377-396). In these previous studies, the effect of racemic halofenate on diabetes was observed when combined with sulfonylureas. A minimal effect on glucose was observed in patients with diabetes treated with racemic halofenate alone. However, significant side effects were noted including gastrointestinal bleeding from stomach and peptic ulcers (see, e.g., Friedberg, S. J. et al., Clin. Res. (1986) Vol. 34, No. 2: 682A).
In addition, there were some indications of drug-drug interactions of racemic halofenate with agents such as warfarin sulfate (also referred to as 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin or Coumadin(trademark) (Dupont Pharmaceuticals, E. I. Dupont de Nemours and Co., Inc., Wilmington, Del. U.S.A.) (see, e.g., Vesell, E. S. and Passantanti, G.T., Fed. Proc. (1972) 31(2): 538). Coumadin(trademark) is an anticoagulant that acts by inhibiting the synthesis of vitamin K dependent clotting factors (which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S). Coumadin(trademark) is believed to be stereospecifically metabolized by hepatic microsomal enzymes (the cytochrome P450 enzymes). The cytochrome P450 isozymes involved in the metabolism of Coumadin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P450 which modulates in vivo drug metabolism of several drugs including the anticoagulant activity of Coumadin(trademark) (see, e.g., Miners, J. O. et al., Bri. J. Clin. Pharmacol. (1998) 45: 525-538).
Drugs that inhibit the metabolism of Coumadin(trademark) result in a further decrease in vitamin K dependent clotting factors that prevents coagulation more than desired in patients receiving such therapy (i.e., patients at risk for pulmonary or cerebral embolism from blood clots in their lower extremities, heart or other sites). Simple reduction of the dose of anticoagulant is often difficult as one needs to maintain adequate anticoagulation to prevent blood clots from forming. The increased anticoagulation from drug-drug interaction results in a significant risk to such patients with the possibility of severe bleeding from soft tissue injuries, gastrointestinal sites (i.e., gastric or duodenal ulcers) or other lesions (i.e., aortic aneurysm). Bleeding in the face of too much anticoagulation constitutes a medical emergency and can result in death if it is not treated immediately with appropriate therapy.
Cytochrome P450 2C9 is also known to be involved in the metabolism of several other commonly used drugs, including dilantin, sulfonylureas, such as tolbutamide and several nonsteroidal anti-inflammatory agents, such as ibuprofen. Inhibition of this enzyme has the potential to cause other adverse effects related to drug-drug interactions, in addition to those described above for Coumadin(trademark) (see, e.g., Pelkonen, O. et al., Xenobiotica (1998) 28: 1203-1253; Linn, J. H. and Lu, A. Y., Clin. Pharmacokinet. (1998) 35(5): 361-390).
Solutions to the above difficulties and deficiencies are needed before halofenate becomes effective for routine treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia. The present invention fulfills this and other needs by providing compounds, compositions and methods for alleviating insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia, while presenting a better adverse effect profile.
This present invention provides a method of modulating Type 2 diabetes in a mammal. The method comprises administering to the mammal a therapeutically effective amount of the (xe2x88x92) stereoisomer of a compound of Formula I, 
wherein R is a member selected from the group consisting of a hydroxy, alkoxy (e.g., OCH2CH3), heteroalkoxy (e.g., OCH2CH2OCH2CH3), aryloxy (e.g., OC6H5), heteroaryloxy (e.g., OC5H4N), lower aralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamido lower alkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, Nxe2x80x2-lower alkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy, halophenoxy substituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-lower alkylamino, N,N-di-lower alkylamino-lower alkylamino, halo substituted lower alkylamino, hydroxy substituted lower alkylamino, lower alkanolyloxy substituted lower alkylamino, ureido, arylsulfonamido (e.g., NHTs), alkylsulfonamido (e.g., NHMs) and lower alkoxycarbonylamino; and X is a halogen; or a pharmaceutically acceptable salt thereof, wherein the compound is substantially free of its (+) stereoisomer.
Some such methods further comprise a compound of Formula II: 
wherein R2 is a member selected from the group consisting of alkyl, heteroalkyl, aryl, heteroaryl, phenyl-lower alkyl, lower alkanamido-lower alkyl, benzamido-lower alkyl, di-lower alkylamino-lower alkyl, ureido-lower alkyl, Nxe2x80x2-lower alkyl-ureido-lower alkyl, carbamoyl-lower alkyl, halophenoxy substituted lower alkyl and carbamoyl substituted phenyl.
Examples of such R2 groups include, without limitation, the following: C1-C5 alkyl, C1-C8-cyclic alkyl, C2-C5 alkenyl, and C2-C5 alkynyl, wherein the groups are optionally substituted with one or more halogen atoms; phenyl, naphthyl and pyridyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, xe2x80x94NO2, xe2x80x94S(O)m(C1-C5alkyl), xe2x80x94OH, xe2x80x94NR3R4, xe2x80x94CO2R5, xe2x80x94CONR3R4, xe2x80x94NR3COR4, xe2x80x94NR3CONR3R4 and xe2x80x94CvFw; xe2x80x94(CHR3)R4; xe2x80x94R7OR3; xe2x80x94R7O2CR8NR3R4, xe2x80x94(CH2)oCH(R3)(CH2)qO2CR9; xe2x80x94(CH2)oCH(R3)(CH2)qNR4COR9; xe2x80x94(CH2)oCH(R3)(CH2)qNR4CONR3R4; xe2x80x94(CH2)oCH(R3)(CH2)qNR4COOR10; xe2x80x94(CH2)oCH(R3)(CH2)qNR4SO2R11; xe2x80x94(CHR3)pCO2R12; xe2x80x94(CHR3)pNR3R4; xe2x80x94(CHR3)sCONR13R14
Subscripts m, o, q, s, t, u, v and w are integers as follows: m is 0 to 2; o and q are 0 to 5; p is 1 to 5; s is 1 to 3; t is 1 to 5; u is 0 to 1; v is 1 to 3; and w is 1 to (2v+1). R3and R4 are independently H, C1-C5 alkyl, phenyl or benzyl. R5 is H, C1-C5 alkyl or NR3R4. R6 is phenyl, naphthyl, pyridyl, imidazolyl, indoxyl, indolizinyl, oxazolyl, thiazolyl, pyrimidyl, or 1-pyrazolyl optionally substituted with one or more substituents selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, xe2x80x94NO2, xe2x80x94S(O)m(C1-C5alklyl), xe2x80x94OH, xe2x80x94NR3R4, xe2x80x94CO2R5, xe2x80x94CONR3R4, xe2x80x94NR3COR4, xe2x80x94NR3CONR3R4 and xe2x80x94CvFw. R7 is a C1-C8 saturated or unsaturated, straight-chain, branched or cyclic alkylene or alkylidene group optionally substituted with one or more groups selected from halo, hydroxyl, thiol, amino, monoalkyl amino, dialkyl amino, acylamino, carboxyl, alkylcarboxyl, acyl, aryl, aroyl, aralkyl, cyano, nitro, alkoxy, alkenyloxy, alkylcarbonyloxy and arylcarbonyloxy. R8 is a C1-C8 straight-chain or branched alkylene or alkylidene optionally substituted with one or more groups selected from amino, monoalkyl amino, dialkyl amino, acylamino, hydroxyl, thiol, methylthiol, carboxyl and phenyl. R9 and R10 are independently H, C1-C5 alkyl, optionally substituted with one or more groups consisting of C1-C5 alkoxy aryl and heteroaryl, wherein the aryl is phenyl or naphthyl optionally substituted with one or more substituents selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, xe2x80x94NO2, xe2x80x94S(O)m(C1-C5alkyl), xe2x80x94OH, xe2x80x94NR3R4, xe2x80x94CO2R5, xe2x80x94CONR3R4, xe2x80x94NR3COR4, xe2x80x94NR3CONR3R4, and xe2x80x94CvFw, and wherein the heteroaryl is pyridyl optionally substituted with one or more substituents selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, xe2x80x94NO2, xe2x80x94S(O)m(C1-C5alkyl), xe2x80x94OH, xe2x80x94NR3R4, xe2x80x94CO2R5, xe2x80x94CONR3R4, xe2x80x94NR3COR4, xe2x80x94NR3CONR3R4 and xe2x80x94CvFw. R11 is methyl or phenyl, wherein the phenyl is optionally substituted with methyl and/or xe2x80x94NO2. R12 is H, C1-C5 alkyl, phenyl, benzyl, naphthyl or pyridyl, wherein the C1-C5 alkyl, phenyl, naphthyl, benzyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, xe2x80x94NO2, xe2x80x94S(O)m(C1-C5alkyl), xe2x80x94OH, xe2x80x94NR3R4, xe2x80x94CO2R5, xe2x80x94CONR3R4, xe2x80x94NR3COR4, xe2x80x94NR3CONR3R4 and xe2x80x94CvFw. R13 and R14 are independently the following: alkyl, alkenyl, aryl, aralkyl or cycloalkyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, xe2x80x94NO2, xe2x80x94S(O)m(C1-C5alkyl), xe2x80x94OH, xe2x80x94NR3R4, xe2x80x94CO2R5, xe2x80x94CONR3R4, xe2x80x94NR3COR4, xe2x80x94NR3CONR3R4xe2x80x94CH2NR3R4, OOCR18 and xe2x80x94CvFw; and wherein R13 and R14 are included as xe2x80x94(CHR3)CONR13R14, NR13R14 is 
R15 is CvFw or C1-C5 alkyl, wherein C1-C5 alkyl is optionally substituted with the following substituents: C1-C5 alkoxy; phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, xe2x80x94NO2, xe2x80x94S(O)m(C1-C5alkyl), xe2x80x94OH, xe2x80x94NR3R4, xe2x80x94CO2R5, xe2x80x94CONR3R4, xe2x80x94NR3COR4, xe2x80x94NR3CONR3R4 and xe2x80x94CvFw; benzyl, optionally substituted with one or more substituents selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, xe2x80x94NO2, xe2x80x94S(O)m(C1-C5alkyl), xe2x80x94OH, xe2x80x94NR3R4, xe2x80x94CO2R5, xe2x80x94CONR3R4, xe2x80x94NR3COR4, xe2x80x94NR3CONR3R4 and xe2x80x94CvFw. R16 is H, C1-C5 alkyl or benzyl. R17 is C1-C5 alkyl, C3-C8 cyclic alkyl, phenyl or benzyl. R18 is H, alkyl, aryl, aralkyl or cycloalkyl, where the group is optionally substituted with one or more substituents selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, xe2x80x94NO2, xe2x80x94S(O)m(C1-C5alkyl), xe2x80x94OH, xe2x80x94NR3R4, xe2x80x94CO2R5, xe2x80x94CONR3R4, xe2x80x94NR3COR4, xe2x80x94NR3CONR3R4 and xe2x80x94CvFw.
Some such methods further comprise a compound of Formula III: 
The preferred compound of Formula III is known as xe2x80x9c(xe2x88x92) 2-acetamidoethyl 4-chlorophenyl-(3-trifluoromethylphenoxy)-acetatexe2x80x9d or xe2x80x9c(xe2x88x92) halofenate.xe2x80x9d
The present invention further provides a method for modulating insulin resistance in a mammal. This method comprises administering to the mammal a therapeutically effective amount of the (xe2x88x92) stereoisomer of a compound of Formula I. Some such methods further comprise a compound of Formula II. Some such methods further comprise a compound of Formula III.
The present invention further provides a method of alleviating hyperlipidemia in a mammal. This method comprises administering to the mammal a therapeutically effective amount of a compound of Formula I. Some such methods further comprise a compound of Formula II. Some such methods further comprise a compound of Formula III.
The present invention further provides a method of modulating hyperuricemia in a mammal. This method comprises administering to the mammal a therapeutically effective amount of a compound of Formula I. Some such methods further comprise a compound of Formula II. Some such methods further comprise a compound of Formula III.
The present invention also provides compounds and pharmaceutical compositions. The compounds are of Formula I, Formula II or Formula III. The pharmaceutical compositions comprise a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I, Formula II or Formula III.